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Compound, preparation method thereof and application of compound in preparation of cabazitaxel

A compound and reaction technology, which is applied in the preparation of chemical drugs and the field of pharmacy, can solve the problems of large amount of solvent usage, complex structure, and many side reactions, and achieve small impact on operators and the environment, simple post-processing, and low solvent usage little effect

Inactive Publication Date: 2013-03-06
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] According to route 1, there are many steps to synthesize cabazitaxel, the yield is low, and there are many side reactions; while the steps to synthesize cabazitaxel according to route 2 are short, but the deprotection group and methylation reaction are carried out after coupling the side chain acid , because the side chain acid groups are relatively large and the structure is relatively complex, which is prone to side reactions such as ring opening and racemization, and produces a lot of impurities. It is difficult to purify through simple column purification, and liquid phase preparation or multiple Sub-column purification, the amount of solvent used is very large, and the yield after purification is also very low

Method used

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  • Compound, preparation method thereof and application of compound in preparation of cabazitaxel
  • Compound, preparation method thereof and application of compound in preparation of cabazitaxel
  • Compound, preparation method thereof and application of compound in preparation of cabazitaxel

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0095] Example 1-1 7,10-di-O-(2,2,2-trichloroethoxycarbonyl)-13-O-acetyl-10-deacetylbaccatin III

[0096] First add 1L of anhydrous toluene to the reaction flask, and mix 100g (0.11mol ) into it, after the dissolution is complete, cool the internal temperature of the reaction solution to 0°C, add 62mL (0.44mol) of triethylamine, continue to maintain the internal temperature at 0°C, and slowly add 15.8mL (0.22mol) of acetyl chloride dropwise to control the reaction The inner temperature of the liquid does not exceed 10°C. After the dropwise addition, keep stirring and react for 0.5h, then raise the temperature to 80°C and keep warm for 24h. A large amount of solids are precipitated. It was determined by TLC that the reaction raw materials had been reacted, slowly poured into saturated aqueous sodium bicarbonate solution, added ethyl acetate to extract the aqueous phase, TLC spot plate confirmed that there was no product remaining in the aqueous phase, washed the organic phase w...

Embodiment 1-2

[0098]Example 1-2 7,10-di-O-(2,2,2-trichloroethoxycarbonyl)-13-O-benzoyl-10-deacetylbaccatin III

[0099] First add 500mL of anhydrous dimethylformamide to the reaction flask, and 50g (56mmol) of 7,10-bis-O-(2,2,2-trichloroethoxycarbonyl)-10-deacetylbaccatin III After the dissolution is complete, cool the internal temperature of the reaction solution to 0°C, first add 31mL (0.22mol) of triethylamine, and then slowly add 13.0mL (0.11mol) of benzoyl chloride dropwise, and control the internal temperature of the reaction solution not to exceed 10°C, after the dropwise addition, keep stirring and react for 0.5h, then raise the temperature to 95°C and keep warm for 24h, a large amount of solids are precipitated. After the reaction was completed, slowly pour it into saturated aqueous sodium bicarbonate solution, add ethyl acetate to extract the aqueous phase, wash the organic phase with water and saturated brine, and dry over anhydrous sodium sulfate. Filter, and evaporate the filt...

Embodiment 1-3

[0101] Example 1-3 7,10-di-O-(2,2,2-trichloroethoxycarbonyl)-13-O-p-methoxybenzoyl-10-deacetylbaccatin III

[0102] Add 350 mL of anhydrous toluene to the reaction flask, dissolve 35 g (39 mmol) of 7,10-bis-O-(2,2,2-trichloroethoxycarbonyl)-10-deacetylbaccatin III into it, and completely After dissolving, cool the internal temperature of the reaction solution to 0°C, first add 22mL (0.16mol) of triethylamine, then slowly add 10.6mL (78mmol) of p-methoxybenzoyl chloride, and control the internal temperature of the reaction solution to not exceed 10°C After the dropwise addition, the reaction was carried out with heat preservation and stirring for 0.5h, and then the temperature was raised to 100°C for 24h with heat preservation, and a large amount of solids were precipitated. After the reaction was completed, slowly pour it into saturated aqueous sodium bicarbonate solution, add ethyl acetate to extract the aqueous phase, wash the organic phase with water and saturated brine, an...

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Abstract

The invention belongs to the field of pharmacy, particularly belongs to the field of the preparation of chemical drugs, and more particularly relates to a compound, a preparation method of the compound and the application of the compound in the preparation of cabazitaxel. In order to provide a cabazitaxel preparation method which is less in side reactions, high in product yield, less in byproducts, high in product quality, low in production cost, and suitable for the industrial production, the invention discloses a compound and a method for synthesizing cabazitaxel by the compound. The method disclosed by the invention is good in technical repeatability, less in solvent use level, lower in cost, and less in influence to operators and environment. According to the invention, the compound only needs to be refined by once or twice by normal reagent, so that the single impurity and the total impurity of midbodies and final products are less than 0.1% respectively, and the compound meets the quality requirement of bulk drug in ICH (international conference on harmonization) in the European union; and the compound can be taken as the raw material of cabazitaxel injection, and is very high in the value and the prospect of the industrial application.

Description

[0001] technical field [0002] The invention belongs to the field of pharmacy, especially the field of preparation of chemical drugs, and more specifically relates to a cabazitaxel intermediate, a preparation method thereof and an application thereof in the preparation of cabazitaxel. [0003] Background technique [0004] Prostate cancer is a common male genitourinary system tumor with a high incidence in Europe and the United States, accounting for the second place among male malignant tumors. According to statistics, about 760,000 new cancer cases were diagnosed in the United States in 2009, of which prostate cancer accounted for about 25%. The incidence of prostate cancer in my country is lower than that in Europe and the United States, but it is also increasing year by year, ranking third among male urogenital malignant tumors. The treatment of prostate cancer mainly includes conservative treatment, surgical treatment, radiotherapy, endocrine therapy, chemotherapy, e...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D305/14
Inventor 赵俊宗在伟王易杜有国刘文杰
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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